Cadmium (Cd) is a heavy metal of high interest to the Superfund Initiative. It has no known physiological function but is a neurotoxicant. Cd exposure is associated with cognitive and olfactory impairment in humans. However, little is known concerning the underlying molecular and cellular mechanisms. This grant explores the molecular and cellular basis for the deleterious effects of Cd on olfaction and cognition in mouse models, with a focus on its effects on adult neurogenesis and signal transduction systems critical for hippocampus- dependent memory. We hypothesize that Cd interferes with adult neurogenesis in the dentate gyrus of the hippocampus and in olfactory bulb, and disrupts signal transduction pathways in neurons critical for learning and memory, including the Ca2+/cAMP/ERK 1/2 MAP kinases/MSK1/CREB signaling pathway. We further hypothesize that these adverse cellular and molecular effects may underlie Cd neurotoxicity in cognition and olfaction. We will test these hypotheses both in primary cultured neural stem cells and in vivo in mice. Studies proposed here will provide new insights concerning mechanisms of Cd neurotoxicity, may establish new mouse models to investigate Cd neurotoxicity, and may shed lights regarding neurotoxicity of other heavy metals. Finally, results from this study may provide useful information for Cd risk assessment and identify adult neurogenesis and components of the Ca2+/ cAMP/ ERK1/2 /MSK1/CREB signaling pathway as sensitive, new biomarkers for Cd neurotoxicity.